Diels-Alder type syntheses intramolecular

The Dess-Martin periodinane 8 is also able to oxidize aromatic compounds to the corresponding quinones. The presence of water is important and, starting from anilides 42 substituted in the 2-position, the rare class of ortho-imido-quinones 43 is accessible, Scheme 21. It has been shown that compounds of type 43 are interesting building blocks and can lead to polycyclic molecules of diverse molecular architecture [95,96]. They can undergo subsequent Diels-Alder reactions and intramolecular versions have been used for a rapid access to natural products and for synthesis of scaffolds for further manipulation.para-Quinones 45 are also easily accessible, however, only in modest yields by reacting 4-sub-stituted anilines 44 under the same reaction conditions, Scheme 21 [97]. 

B. R. Bear, S. M. Sparks, K. J. Shea, The Type 2 Intramolecular Diels-Alder Reaction Synthesis and Chemistry of Bridgehead Alkenes Angew. Chem. Int. Ed. Engl. 2001, 40, 820-849. 

Tetracyclization. The Heathcock group1 has described a remarkably short and efficient synthesis of the skeleton of Daphniphyllum alkaloids (2) by reaction of the dialdehyde 1 with gaseous ammonia and then dissolution in acetic acid at 70°. The yield is 77%, based on the diol precursor to 1. The azadiene a and the imine b have both been isolated and identified. The conversion of a to b is an intramolecular Diels-Alder type reaction. The tetracyclization may well be involved in the biosynthesis of alkaloids such as Daphnilactone A (3). 

Methods for the synthesis of central hydroisoquinolines or pyrrolo-hydroisoquinoHnes of manzamine A can be classified into 11 types of reactions (1) intermolecular Diels-Alder reaction, (2) intramolecular Diels-Alder reaction, (3) photochemical reaction, (4) radical reaction, (5) ionic cyclization, (6) intramolecular Michael reaction, (7) intramolecular Maimich reaction, (8) intramolecular [3 + 2] cycloaddition, (9) intermolecular [3 + 2] cycloaddition, (10) Pauson-Khand reaction, and (11) eneyne metathesis. 

There are many types of Diels-Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

Camphor sultam derivatives have proved to be effective chiral auxiliaries in many different types of asymmetric reactions. As shown in Scheme 5-44, chiral camphor sulfam can be applied in the synthesis of (—)-pulo upone precursor 151 using an intramolecular Diels-Alder reaction. A Wittig reaction of 148 with 147 connects the chiral auxiliary to the substrate, and subsequent intramolecular Diels-Alder reaction via transition state 150 affords product 151. Compound 151 already has the stereochemistry of (—)-pulo upone 153.72... 

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

The intramolecular Diels-Alder reaction of l-(A -a -alkenyl)-2(l//)-pyrazinones generates m-[l,7]naphthyridines in good yields (Scheme 62) <2001TL7397>. This method has been used in the development of a r-[l,7]naphthyr-idine-based scaffold on which to build a type VI external /3-turn mimic <2003EJ01868>, and for the synthesis and conformational analysis of [l,7]naphthyridine-based substance P antagonist analogues <2003T4721>. 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

The phyllocladane skeleton 131 was constructed efficiently by stereoselective formations of six carbon-carbon bonds and four rings via a one-pot sequence of cyclizations the ene type, [2+2+2], and [4+2] cycloadditions. In this synthesis, the Conia ene reaction of 127 takes place under mild conditions to generate 128, and the cyclotrimerization of its diyne with 118 gives 129. These two reactions are catalysed by CpCo(CO)2. Finally, ring-opening to give 130 and intramolecular Diels-Alder reaction in the presence of DPPE produced the phyllocladane skeleton 131 in a total yield of 42% [55]. 

For fiirther reactions of this type see <95CC2025>. The synthesis of l,4-dihydrofurano[3,4-d]-3,2-oxathiine-2-oxides, precursors for nonclassical heteroaromatic o-quinodimethanes, and their application in the Diels-Alder reaction were reported <95CC2537>. The intramolecular Diels-Alder reaction with furans (e. g., 47) offers a rapid access to highly functionalized isoquinolines <95 JCS(P 1)2393>. 

Lauchli and Shea have recently published a synthesis of the welwistatin core based on the use of a type 2 intramolecular Diels-Alder (T2IMDA) reaction... 

Diels-Alder reactions have been widely used to synthesize lignans, particularly the arylnaphthalene and aryltetralin types. This was one of the first examples of the use of an znfermolecular (as opposed to an intramolecular) Diels-Alder reaction for lignan synthesis. The approach includes the use of an arylisobenzofuran (Fig. 4) generated in situ as diene and dimethylacetyl-enedicarboxylate (DMAD) as the dienophile (Fig. 4). The Diels-Alder prod-... 

An elegant application of this photocycloaddition in the field of triquinane synthesis has been reported by Reddy and Rawal [160]. The initially formed oxetane 163, formed from the Diels-Alder adduct 162, is easily cleaved reductively (by use of LiDBB = lithium di-/er -butyl-biphenylide) to give 164. This approach was also used for the construction of structurally diverse di- and (propellane-type as well as linear or angular anellated) triquinanes [161]. The classic linear triquinane hirsutene is also available via this route [162]. Star-like molecules like the tiene 167 are available via a sequence of intramolecular photocycloaddition (from the 1,3-cyclohexadiene/acylallene adduct 165) and oxetane (166) ring-opening (Sch. 58) [163]. Further examples of intramolecular... 

TOTAL SYNTHESIS OF BIOLOGICALLY INTRIGUING DRIMANE-TYPE SESQUITERPENOIDS VIA INTRAMOLECULAR DIELS-ALDER APPROACHES... 

A type 2 intramolecular /V-acylnitroso Diels-Alder reaction of hydroxamic acid 177 followed by catalytic hydrogenation of the double bond was employed for the synthesis of substituted bridged bicyclic derivative 178, as a single diastereomer (Scheme 75 <2002OL2637>). Cleavage of the N-O bond was performed by reduction with Na(Hg) amalgam and provided m-3,7-disubstituted azocane 9, as a single isomer in 80% yield. 

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